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PubMed2003

Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by an acquired immune defect that can cause autoimmune complications, including anemia and thrombocytopenia. We conducted an observational study of the epidemiology, clinical presentation and significance of autoimmune complications of CLL/SLL in 132 patients from a large population (>45,000 veterans), in which at least 90% of patients with CLL/SLL have been previously identified. Over a period of 12.5 years, 12 patients (9.1%) had autoimmune complications; of these, 6 (4.5%) had autoimmune hemolytic anemia (AIHA), 5 (3.8%) had immune thrombocytopenia (ITP), and 1 (0.8%) had pure red blood cell aplasia (PRBA). All 6 cases of AIHA had a positive direct immunoglobulin test for IgG and C3d. In 6 patients, CLL/SLL was an incidental finding at the time of presentation with autoimmune cytopenia. Nine out of 10 patients responded to immunosuppressive therapy, which was complicated by serious infection in 7 cases, one of which was fatal. The major cause of mortality in patients with autoimmune complications of CLL/SLL was secondary malignancy. Survival of patients with immune cytopenia was not significantly different from CLL/SLL patients without immune cytopenia. Among patients with anemia or thrombocytopenia, mortality was significantly higher in those with bone marrow failure compared to an autoimmune etiology. We show that in a non-referred population with a high incidence of CLL/SLL, autoimmune cytopenia can occur early in the natural history of the disease. These data suggest that the Rai and Binet classifications for CLL need to be modified for patients with autoimmune cytopenia. .

Aged↗

PubMed1990

Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients.

Human leukocyte antigen-D region-related alleles (human leukocyte antigen DR and DQ) and human leukocyte antigen class I alleles were typed serologically in 31 Japanese patients with autoimmune hepatitis. These patients had increased serum levels of AST and IgG, high titers of autoantibodies, no history of blood transfusion and were negative for HBsAg and antibodies to HBc. Three hundred eighty-six healthy subjects and 30 patients with cryptogenic chronic hepatitis served as control groups. The frequency of DR4 was significantly higher in autoimmune hepatitis patients (90.3%) than in healthy subjects (38.6%) and in cryptogenic chronic hepatitis patients (30%). The frequency of Bw54 was significantly higher in autoimmune hepatitis patients (45.2%) than in healthy subjects (10.9%). The risk to DR4-positive subjects for autoimmune hepatitis was 14.8 relative to healthy subjects. Two of 31 patients (6.5%) with autoimmune hepatitis were positive for antibody to hepatitis C virus; both clearly satisfied criteria for autoimmune hepatitis and both had Bw54 and DR4. This study revealed a highly significant association of autoimmune hepatitis with human leukocyte antigen Bw54 and DR4 in Japanese patients. Among the DR4-positive patients with autoimmune hepatitis, no significant differences were seen between those positive or negative for Bw54 with regard to clinical or laboratory data, relapse of disease or efficacy of prednisolone. Thus human leukocyte antigen class II alleles contribute to susceptibility and resistance to autoimmune hepatitis in Japanese patients, with distinct racial differences from those in white patients.

Adult↗

PubMed1993

Cirrhosis of undefined pathogenesis: absence of evidence for unknown viruses or autoimmune processes.

To examine whether unknown viruses or autoimmune processes contribute to the development of cryptogenic liver disease, we studied 48 patients undergoing liver transplantation who had non-A, non-B cirrhosis; non-blood-borne cirrhosis of unknown etiology; or autoimmune cirrhosis. After the diagnosis of hepatitis C virus infection was established by the presence of viral antibodies or viral RNA, patients were reclassified into three groups: hepatitis C virus infection, autoimmune cirrhosis and cryptogenic cirrhosis. Explant histological appearance, incidence of posttransplant hepatitis and immunological features were compared in the three groups. Thirty-one percent of patients had neither hepatitis C virus infection nor classical autoimmune cirrhosis and were classified as having cryptogenic cirrhosis. Unlike histological appearance in hepatitis C virus infection but similar to that in autoimmune cirrhosis, explant histological appearance of cryptogenic cirrhosis showed inactive cirrhosis with little inflammation. After transplantation, histological hepatitis of the allograft was demonstrated in 44% of patients with hepatitis C infection but in no patient with autoimmune or cryptogenic cirrhosis. The autoimmune score, developed from clinical criteria associated with autoimmune liver disease, was significantly lower in cryptogenic cirrhosis and hepatitis C virus infection than in autoimmune cirrhosis. Autoantibodies--including antinuclear antibodies, smooth muscle antibodies and liver-kidney microsomal antibodies--were not commonly present in serum of patients with cryptogenic cirrhosis, whereas antibodies to soluble liver antigens were found with increased frequency in this entity. We conclude that in many patients with liver disease, no pathogenesis can be identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune Diseases↗

PubMed1996

Th2 and Th1 autoreactive anti-class II cell lines in the rat suppress or induce autoimmunity.

It is now currently thought that Th1 autoreactive cells may induce organ specific autoimmune disease and in these situations Th2 cells are considered as regulatory cells. However, in other situations Th2 cells may be pathogenic. Thus, some chemicals (HgCl2, gold salts or D-penicillamine) may induce Th2-mediated systemic autoimmune disorders in susceptible Brown-Norway (BN) rats. In contrast, HgCl2 induces non antigen specific immunosuppression in Lewis (LEW) rats and protects this strain against organ-specific autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). Anti-self MHC class II T cells have been detected in both susceptible and resistant strains upon exposure with these chemicals. Autoreactive T cell lines that recognize self MHC class II molecules have been derived from gold salt-injected BN rats (BNAu lines) and from HgCl2-injected LEW rats (LEWHg lines). BNAu T cell lines produced IL-4 and transferred antibody-mediated autoimmunity in BN rats deprived of CD8+ cells. In contrast, HgCl2 protects susceptible rats from Th1-mediated autoimmunity, (autoimmune uveoretinitis). LEWHg lines produced IL-2, IFN-gamma and TGF-beta and were able to protect LEW rats against cell-mediated autoimmunity (EAE) and (LEW x BN)F1 hybrids from antibody-mediated, HgCl2-induced autoimmunity. Several points will be discussed: the specificity of these autoreactive T cells, the mechanisms by which chemicals may induce these cells and the mechanisms by which the immune system maintains or reestablishes self tolerance in rats exposed to these agents.

Animals↗

PubMed2001

Clinical indications and biological mechanisms of splenic irradiation in autoimmune diseases.

BACKGROUND: Splenic irradiation (SI) is a fairly unknown treatment modality in autoimmune disorders like autoimmune thrombocytopenia (AIT) or autoimmune hemolytic anemia (AIHA), which may provide an effective, low toxic and cost-effective treatment for selected patients. PATIENTS, MATERIALS AND METHODS: This article reviews the limited experiences on splenic irradiation in autoimmune thrombocytopenia by analyzing the current studies including 71 patients and some preliminary reports on splenic irradiation in autoimmune hemolytic anemia. RESULTS: In autoimmune thrombocytopenia between 40 and 90% of all patients responded, but most of them relapsed within 4 to 6 months after splenic irradiation. Between 10 and 20% of all patients had a sustained response. The efficacy of splenic irradiation in HIV-associated cases of thrombocytopenia is probably lower than in other forms of autoimmune thrombocytopenia, but especially in this group immunosuppressive drug treatment of autoimmune thrombocytopenia exposes some problems. In autoimmune hemolytic anemia there are some case reports about efficacy of splenic irradiation. Toxicity of splenic irradiation in both diseases was very moderate. CONCLUSIONS: For HIV patients, for elderly patients or patients at high risk for complications following splenectomy splenic irradiation might be a treatment option. Splenic irradiation as preoperative treatment in patients not responding to or not suitable for immunosuppressive drugs prior to splenectomy may be a promising new application of splenic irradiation to reduce adverse effects of splenectomy in thrombocytopenic patients. A further analysis of the biological mechanisms underlying splenic irradiation may help to improve patient selection, to optimize dose concepts and treatment schedules and will improve understanding of radiotherapy as an immunomodulatory treatment modality.

Age Factors↗

PubMed2000

Antinuclear antibody (ANA) and ANA profile tests in children with autoimmune disorders: a retrospective study.

The study objective was to determine the clinical value of positive antinuclear antibody (ANA) and ANA profile tests in children with autoimmune disorders. A retrospective chart review was carried out of all patients under 18 years of age with a positive ANA test (HEp-2 cell substrate, titre > or =1:40) and ANA profile (ELISA) referred to the paediatric rheumatology service at the authors' institution between 1992 and 1996. Of 245 children with a positive ANA test, 134 (55%) had an autoimmune disease, including juvenile rheumatoid arthritis (n = 49), systemic lupus erythematosus (SLE) (n = 40) and others (n = 45). The remaining 111 patients did not have identifiable autoimmune diseases. Patients with autoimmune disorders had significantly higher ANA titres of > or = 1:160 (chi2 = 16, P<0.0001). In addition, of the 245 patients with a positive ANA test, 86 had an ANA profile performed; this was positive in 32 and negative in 54. All 32 patients with a positive ANA profile (100%) had an autoimmune disorder, compared to 22 (41%) of 54 with a negative ANA profile who had autoimmune disorders. Of 22 SLE patients with a positive ANA profile, 16 (73%) had positive anti-dsDNA and 15 (68%) had positive anti-Sm and positive anti-RNP. A positive ANA profile correlated strongly with an ANA titre > or = 1:640 (chi2 = 5.7 , P<0.02). The study demonstrated that only 55% of children with a positive ANA test had a definitive diagnosis of autoimmune disorder. These children tend to have higher ANA titres of > or =1:160. However, a positive ANA profile was strongly correlated with an ANA titre > or =1:640 and highly indicative of an autoimmune disorder (100%). We suggest that in order to reduce cost, an ANA profile should not be performed on all patients with positive ANA, but reserved for those with an ANA titre of > or =1:640 and/or those with a high clinical index of suspicion for autoimmune disorder, especially SLE.

Antibodies, Antinuclear↗

PubMed2004

Frequency and significance of anti-glutathione S-transferase autoantibody (anti-GST A1-1) in autoimmune hepatitis.

Several phase I and phase II multi-drug metabolizing enzymes, such as CYP2D6, 3A4, and UGTA1, were reported to act as immunotargets in a subset of autoimmune hepatitis and hepatic autoimmunity. However, it is uncertain whether glutathione S-transferase (GST) A1-1, one of the phase II multi-drug metabolizing enzymes, is also an immunotarget in autoimmune hepatitis. So, in the present study, we investigated the frequency and significance of anti-GST A1-1 in sera from patients with autoimmune hepatitis. A total of 74 serum samples from patients with autoimmune hepatitis were examined in the present study. As controls, 20 serum samples from patients with primary biliary cirrhosis, 10 serum samples from patients with primary sclerosing cholangitis, 40 serum samples from patients with liver cirrhosis type B and C, 32 serum samples from patients with systemic lupus erythematosus, and 20 serum samples from normal controls were used. Anti-GST A1-1 antibody was determined by immunoblotting using the recombinant full-length GST A1-1 protein as the antigen. The immunofluorescent staining pattern of anti-GST A1-1 was investigated using rat liver and kidney sections. We compared clinicopathologic findings between anti-GST A1-1-positive and -negative autoimmune hepatitis patients. Anti-GST A1-1 was detected in 12 (16%) of 74 patients with autoimmune hepatitis, however, it was not detected in any control serum samples except for two patients with primary biliary cirrhosis. The immunofluorescence staining pattern of anti-GST A1-1 was found to be unique and different from those of anti-mitochondrial antibody or anti-liver-kidney microsome type 1 antibody. Anti-GST A1-1 coexisted with other autoantibodies such as anti-nuclear or anti-smooth muscle antibodies, but did not coexist with anti-soluble liver antigen/liver pancreas. Anti-GST A1-1-positive autoimmune hepatitis patients had severe clinical features and a poor prognosis compared with anti-GST A1-1-negative patients. These findings suggested that despite the low frequency, anti-GST A1-1 might be the marker of an early progression in autoimmune hepatitis.

Adult↗

PubMed2004

Analysis of the threshold liability model provides new understanding of causation in autoimmune diseases.

Autoimmune diseases include a heterogeneous group of complex traits, the causes of which are essentially unknown. The threshold liability model is a hypothesis that has a significant influence on thinking about causation in these diseases. Here, I analyze this model and assess its utility in understanding causation in autoimmunity. According to the model, members of a population have a normal distribution of genetic liability for a particular autoimmune disease. Further, a threshold value exists for each autoimmune disease such that an individual develops disease when his/her liability exceeds the threshold value; environmental and stochastic factors and epistatic gene interactions may increase or decrease an individual's disease liability. There are, however, two main problems with the threshold liability model. First, for a particular autoimmune disease, the threshold value divides a population into two distinct groups that consist either of affected or of healthy individuals. I show that this dichotomous division is inaccurate and misleading. Second, the threshold value corresponds to the occurrence of a component-cause of disease, i.e. when an appropriate collection of causative factors for a particular autoimmune disease is present, the disease must inevitably occur. I argue, however, that the disease contribution of essentially unknown random or stochastic factors to causation is at least similar in importance to the contributions of genetic and environmental factors. These stochastic factors add a significant element of unpredictability to the effects of genetic and environmental factors. Consequently causes in autoimmunity do not act deterministically, which is implied by the component-cause concept. Instead, the role of causative factors is to alter disease risk. I therefore reject the threshold liability model and conclude that a probabilistic approach provides the only reasonable way to understand causation in autoimmune diseases. This conclusion has important implications for other deterministic hypotheses in autoimmunity including other component-cause hypotheses.

Autoimmune Diseases↗

PubMed2001

Virus-induced autoimmunity: epitope spreading to myelin autoepitopes in Theiler's virus infection of the central nervous system.

Epidemiological studies indicate that host immunogenetics and history of infection, particularly by viruses, may be a necessary cofactor for the induction of a variety of autoimmune diseases. To date, however, there is no clear-cut evidence, either in experimental animal models or in human autoimmune disease, that supports either molecular mimicry (Wucherpfennig and Strominger, 1995; Fujinami and Oldstone, 1985) or a role for superantigens (Scherer et al., 1993) in the initiation of T cell-mediated autoimmunity. In contrast, the current data provide compelling evidence in support of a major role for epitope spreading in the induction of myelin-specific autoimmunity in mice persistently infected with TMEV. It is significant that two picornaviruses closely related to TMEV, coxsackievirus (Rose and Hill, 1996) and encephalomyocarditis virus (EMCV) (Kyu et al., 1992), have been similarly shown to persist (either the viral RNA or the infectious virus) in their target organs and have been associated with the development of chronic autoimmune diseases, including myocarditis and diabetes. Thus, inflammatory responses induced by viruses that trigger proinflammatory Th1 responses, and have the ability to persist in genetically susceptible hosts, may lead to chronic organ-specific autoimmune disease via epitope spreading. Epitope spreading has important implications for the design of antigen-specific therapies for the potential treatment of MS and other autoimmune diseases. This process indicates that autoimmune diseases are evolving entities and that the specificity of the effector autoantigen-specific T cells varies during the chronic disease process. Our experiments employing tolerance in R-EAE clearly indicate that antigen-specific treatment of ongoing disease is possible for preventing disease relapses, provided the proper relapse-associated epitope is targeted (Vanderlugt et al., 1999). However, the ability to identify relapse-associated epitopes in humans will be a difficult task because immunodominance will vary in every individual. The use of costimulatory antagonists that can induce anergy without requiring prior knowledge of the exact epitopes (Miller et al., 1995b), or the use of therapies that induce bystander suppression (Nicholson et al., 1997; Brocke et al., 1996), may thus be more practical current alternative therapies for the treatment of human autoimmune disease.

Animals↗

PubMed1984

Antigen specific suppressor cell function in autoimmune chronic active hepatitis.

An indirect migration inhibition assay has been used to show that lymphocytes from 26 of 29 patients with autoimmune chronic active hepatitis (CAH) generated T lymphocyte migration inhibitory factors (T-LIF) in the presence of liver specific protein (LSP), compared with only 1 of 21 patients with HBsAg-positive chronic liver disease and none of 19 controls. Generation of T-LIF activity in response to LSP was not observed in any of 5 patients with autoimmune thyroid disease although their T lymphocytes did generate T-LIF activity in the presence of thyroid membrane antigens. T lymphocytes from 1 patient with autoimmune liver and thyroid disease generated T-LIF activity in the presence of both LSP and thyroid membrane antigens. The generation of T-LIF activity by T cells from autoimmune CAH patients was suppressed when these cells were co-cultured in a 9:1 ratio with T cells from normal subjects and patients with HBsAg-positive chronic liver disease, but was unaffected if co-cultured with T cells from other patients with autoimmune CAH. T cells from patients with autoimmune CAH did, however, suppress the generation of T-LIF activity by T lymphocytes from patients with autoimmune thyroid disease when these cells were cultured with thyroid membrane antigens. After pretreatment with cimetidine or mitomycin-C for 30 min, T cells from normal subjects lost their ability to inhibit the generation of T-LIF activity to T lymphocytes from autoimmune CAH patients. These results are consistent with the hypothesis that there exists a defect in the specific suppressor T cell population controlling the immune response to LSP in autoimmune CAH which is unaffected by disease activity and treatment and which may be of fundamental importance in the pathogenesis of the disease.

Adult↗

PubMedDate not supplied

Autoimmune ovarian failure: comparing the mouse model and the human disease.

The neonatal-thymectomy-induced mouse model of autoimmune oophoritis has two important similarities with human autoimmune oophoritis. First, in both cases there is some defect in the immune system that permits the development of organ-specific autoimmunity. Second, in both there is some ovarian target under attack. In neither case do we fully understand the nature of the immune defect or the ovarian target. Because of its strong analogy with the human disease, murine experimental postthymectomy autoimmune oophoritis may provide insight into the pathogenesis of autoimmune premature ovarian failure in women. Such studies may open new avenues toward the development of specific diagnostic and therapeutic methods. The histologic distribution of the ovarian lymphocytic infiltration is similar in the mouse and the human, and both mice and women with the disorder have reduced natural killer cell activity. Furthermore, susceptibility in both mice and women appears to be associated with genes outside the major histocompatibility complex. Finally, the mouse disorder is associated with a persistent neonatal-like Th2 response that suggests possible similarities with autoimmune polyglandular failure type 1 in humans. There is no currently available validated serum antibody marker that will confirm a clinical diagnosis of autoimmune premature ovarian failure. While investigating this animal model we cloned a novel gene that encodes an ooplasm-specific antigen associated with autoimmune oophoritis in mice. Based on its role in preimplantation development, we have designated this antigen Maternal Antigen That Embryos Require (MATER). MATER provides a new determinant with which to investigate the mechanisms of autoimmune premature ovarian failure.

Animals↗

PubMed2004

Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis is a common cause of chronic hepatitis, and acute presentation is thought to be uncommon. The aim of this study was to compare clinical, biochemical, and histological features in patients with autoimmune hepatitis presenting with either acute or chronic hepatitis. METHODS: Retrospective review of all patients with autoimmune hepatitis presenting to a University medical center from 1993 to 2002. RESULTS: One hundred fifteen patients with autoimmune hepatitis were identified. Ten patients with autoimmune hepatitis were identified as having acute presentation (group I), and 20 patients with a classic presentation as chronic hepatitis (group II) served as age- and sex-matched controls. All patients met criteria published by the International Autoimmune Hepatitis Group. Patients with acute presentation differed significantly with regard to encephalopathy, albumin levels, and bilirubin levels. Blinded liver biopsy review demonstrated that those with acute presentation had significantly less fibrosis, and significantly greater interface hepatitis, lobular disarray, lobular hepatitis, hepatocyte necrosis, zone III necrosis, and submassive necrosis. CONCLUSIONS: In our study, patients with an acute presentation of autoimmune hepatitis differed from patients with a classical presentation clinically, biochemically, and histologically. In our review, a majority of patients with acute autoimmune hepatitis presented with fulminant hepatic failure. The pattern of zone 3 necrosis may be a specific finding in those with acute autoimmune hepatitis.

Acute Disease↗

PubMed2002

Immunopathogenesis, loss of T cell tolerance and genetics of autoimmune gastritis.

Over the past 10 years experimental autoimmune gastritis has been established as a highly defined model of organ-specific autoimmunity. Autoimmune gastritis represents one of the few autoimmune diseases in which the causative autoantigens, namely the gastric H/K ATPase alpha- and beta-subunits, are defined. Furthermore, it has been clearly established that a CD4+ T cell response to the H/K ATPase beta-subunit, in particular, is essential for the initiation of autoimmune gastritis. The immunopathology of autoimmune gastritis is due to a disruption of the normal developmental pathways of the mucosa, rather than a direct depletion of the end-stage parietal and zymogenic cells. CD4+CD25+ regulatory T cells were first described in experimental autoimmune gastritis and there has been a recent explosion of interest in the potential role of these immunoregulatory T cells in protection against a variety of autoimmune diseases. The availability of H/K ATPase deficient mice has begun to provide considerable insight into the basis for tolerance to the gastric autoantigens. Experimental autoimmune gastritis has also provided valuable insight into our understanding of the genetics of disease susceptibility and four distinct genetic regions have been identified which confer susceptibility to this organ-specific disease. The highlights of these recent advances are the subject of this review.

Animals↗

PubMed1997

DNA vaccines for the treatment of autoimmune disease.

DNA vaccines represent one of the most significant developments in vaccine technology in recent years. Although, in general, studies have primarily focused on the induction of protective immune responses against infectious pathogens, the technology may prove useful for other immune-related diseases, including autoimmunity. Autoimmune disease results from a breakdown in tolerance to self antigens; however, the same fundamental immunological reactions that control immune responses to foreign antigens are also likely to operate during the course of autoimmune disease. These include the reciprocal regulation of Th cell subsets. Th1 cells appear to be involved in many organ-specific autoimmune diseases while suppression of disease is associated with cells of the Th2 phenotype. It has been possible, therefore, to suppress many of the pathological consequences of autoimmunity by manipulating the Th1/Th2 cell balance. The induction of Th2 responses by DNA immunization might therefore be expected to have a profound effect on the course of autoimmune disease. Indeed, we have demonstrated that DNA immunization can protect animals against the autoimmune central nervous system inflammatory disease, experimental autoimmune encephalomyelitis (EAE). As many other autoantigens have now been identified, the application of this technology to other autoimmune diseases warrants investigation.

Animals↗

PubMed2006

IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis.

Autoimmune pancreatitis typically produces an enlarged pancreas with narrowing of the pancreatic duct, and can mimic carcinoma. Autoimmune pancreatitis usually responds to corticosteroid treatment, making it important to differentiate from pancreatic ductal adenocarcinoma. Affected patients often have an elevated serum IgG4. It has been proposed that increased numbers of IgG4-positive plasma cells in tissue might be a marker for the condition. We investigated the role of IgG4 staining in the diagnosis of autoimmune pancreatitis, first in resected pancreas specimens (29 autoimmune pancreatitis, nine chronic alcoholic pancreatitis and 25 pancreatic cancer), then in pancreatic needle biopsies. Immunohistochemical stains for IgG4 were scored as none, mild, moderate or marked, according to published criteria. Moderate to marked numbers of IgG4-positive plasma cells were seen in 21/29 autoimmune pancreatitis patients, and were distributed in and around ducts, in interlobular fibrous tissue and in peripancreatic fat. In contrast, eight of nine examples of chronic alcoholic pancreatitis and 22/25 ductal adenocarcinomas had scores of none or mild. When we subdivided autoimmune pancreatitis into the histologic subtypes lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-destructive pancreatitis, 16/17 lymphoplasmacytic sclerosing pancreatitis had moderate to marked staining, compared to five to 12 idiopathic duct-destructive pancreatitis. Needle biopsies from nine patients suspected of having autoimmune pancreatitis had increased numbers of IgG4 cells. We conclude that pancreatic tissue from patients with autoimmune pancreatitis often shows moderate or marked infiltration by IgG4-positive plasma cells (>10/HPF). This is particularly so in the subtype we have designated lymphoplasmacytic sclerosing pancreatitis. We rarely see IgG4 staining in patients with chronic alcoholic pancreatitis and pancreatic ductal adenocarcinoma. IgG4-positive plasma cells are a useful marker for the tissue diagnosis of autoimmune pancreatitis.

Adenocarcinoma↗

PubMed2002

HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population.

BACKGROUND & AIMS: Autoimmune pancreatitis is a distinctive disease entity characterized by high serum immunoglobulin G4 concentrations. Because of the close association between some autoimmune diseases and particular alleles of major histocompatibility complex genes, we investigated the association between HLA alleles and autoimmune pancreatitis. METHODS: HLA-A, -B, -C, -DR, and -DQ gene typing and HLA-DRB1, -DQB1, and -DPB1 allele typing were performed by the polymerase chain reaction sequence-specific primers method and the restriction fragment length polymorphism method, respectively, in 40 patients with autoimmune pancreatitis, 43 patients with chronic calcifying pancreatitis, and 201 healthy subjects. RESULTS: In patients with autoimmune pancreatitis compared with healthy subjects, we found a significant increase in DR4 (73% vs. 44%, corrected P = 0.01) and DRB1*0405 (58% vs. 21%, corrected P = 0.000026) and DQ4 (58% vs. 26%, corrected P = 0.001) and DQB1*0401 (58% vs. 21%, corrected P = 0.000017). The DRB1*0405-DQB1*0401 haplotype in autoimmune pancreatitis showed no significant association with any HLA class I antigens, in contrast to the B54-DRB1*0405-DQB1*0401 haplotype reported in autoimmune hepatitis. The frequencies of DRB1*0405 and DQB1*0401 were significantly high in patients with autoimmune pancreatitis compared with chronic calcifying pancreatitis. CONCLUSIONS: It is probable that DRB1*0405-DQB1*0401 haplotype is associated with autoimmune pancreatitis in the Japanese population.

Adult↗

PubMed2006

Prognostic significance of autoimmunity during treatment of melanoma with interferon.

BACKGROUND: Immunotherapy for advanced melanoma induces serologic and clinical manifestations of autoimmunity. We assessed the prognostic significance of autoimmunity in patients with stage IIB, IIC, or III melanoma who were treated with high-dose adjuvant interferon alfa-2b. METHODS: We enrolled 200 patients in a substudy of a larger, ongoing randomized trial. Blood was obtained before the initiation of intravenous interferon therapy, after 1 month of therapy, and at 3, 6, 9, and 12 months. Serum was tested for antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies, and patients were examined for vitiligo. RESULTS: The median duration of follow-up was 45.6 months. Relapse occurred in 115 patients, and 82 patients died. The median relapse-free survival was 28.0 months, and the median overall survival was 58.7 months. Autoantibodies and clinical manifestations of autoimmunity were detected in 52 patients (26 percent). The median relapse-free survival was 16.0 months among patients without autoimmunity (108 of 148 had a relapse) and was not reached among patients with autoimmunity (7 of 52 had a relapse). The median survival was 37.6 months among patients without autoimmunity (80 of 148 died) and was not reached among patients with autoimmunity (2 of 52 died). In univariate and multivariate regression analyses, autoimmunity was an independent prognostic marker for improved relapse-free survival and overall survival (P<0.001). CONCLUSIONS: The appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with interferon alfa-2b is associated with statistically significant improvements in relapse-free survival and overall survival in patients with melanoma.

Adjuvants, Immunologic↗

PubMed2004

Accelerated autoimmune disease in MRL/MpJ-Fas(lpr) but not in MRL/MpJ following immunization with high load of syngeneic late apoptotic cells.

Numerous studies have shown that autoantigens may be clustered in the blebs of apoptotic cells. However, it is not yet clear in what circumstances apoptotic cells could be immunogenic rather than tolerogenic when interacting with macrophages, dendritic cells, and B cells. In order to further study this question we compared immunization of high load of syngeneic late apoptotic cells in two genetically close pro-autoimmune mice strains: MRL/MpJ and MRL/MpJ-Fas(lpr). We show that high apoptotic load could accelerate the generation of anti-dsDNA and anticardiolipin, and the extent of kidney disease, in MRL/MpJ-Fas(lpr) but could not generate autoimmunity in MRL/MpJ. Thus, in this model, a high load of apoptotic cells could augment the autoimmune response in established autoimmunity, but did not generate de novo autoimmune response in pro-autoimmune mice. Taken together with previous observations, apoptotic cell load may modify autoimmune disease generating either immune inhibition and down regulation of autoimmunity or immune stimulation and acceleration of an autoimmune disease.

Animals↗